Field of Invention
The present invention relates to a nanocomplex. More particularly, the present invention relates to an immunostimulatory nanocomplex with electric property holds a dengue viral protein inside for inducing immune responses efficiently.
Description of Related Art
Dengue fever, also known as breakbone fever, is an acute viral disease transmitted by Aedes aegypti or Aedes albopictus, and its symptoms include fever (39° C.-40° C.) or aversion to cold, skin rash with fatigue in limb, muscle pains, frontal headache, orbital pain, abdominal pain, backache (i.e. the origin of the term “breakbone fever”), sore throat, and maybe vomiting, fainting, etc. The commonly mentioned dengue fever is classic dengue fever, also called as primary dengue fever. In addition, severe and life-threatening dengue fever characterized by hemorrhage or shock may be developed, also called dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), or secondary dengue fever. It is estimated that there are about 50 million to 100 million cases of dengue infection worldwide each year, with about 250,000 to 500,000 cases of dengue hemorrhagic fever. Hence, the prevention and treatment of dengue fever is an important issue for the governments of many countries. Since dengue virus is the major pathogen of dengue disease, the early detection or prevention with effective vaccine can efficiently control morbidity and death rates of dengue fever.
Please refer to the Taiwan Patent Publication No. 201210614 and its corresponding U.S. patent Ser. No. 13/230,273 “Dengue vaccine, medicinal composition comprising the same, and nucleotide sequence”, and the Taiwan Patent Publication No. 201210615 and its corresponding U.S. patent Ser. No. 13/230,209 “Dengue vaccine, medicinal composition comprising the same, nucleotide sequence, and antibody composition”, which are applied by the inventors of the present invention. Taiwan Patent Publication No. 201210614 and its corresponding U.S. patent Ser. No. 13/230,273, and Taiwan Patent Publication No. 201210615 and its corresponding U.S. patent Ser. No. 13/230,209 are incorporated herein by reference. A dengue vaccine causing no autoimmunity to avoid the cross-reaction between endothelial cell and platelets and being able to shorten the bleeding time is disclosed in the foregoing applications, the contents of which are hereby incorporated by reference herein. The foregoing dengue vaccine has prospective effect in actual operation, but there is deficiency due to the aluminum hydroxide gel (also called as immunostimulant) as an adjuvant in the foregoing dengue vaccine. The ability of the aluminum hydroxide is undesired to enhance the immune response in the organism.
Commonly, the adjuvant action mechanism generally comprises: (a) increasing the life or the immunity of an antigen in the vaccine, (b) delivering antigen to the antigen-presenting cell, (c) improving antigen display in antigen-presenting cell, and (d) inducing the production of immunoregulatory cytokine. The mineral adjuvant is one of the common adjuvant, such as metal salts of zinc, calcium, cerium, chromium, iron, and beryllium. The aluminum salts, such as aluminum hydroxide and aluminum phosphate, is the most commonly used, and is also called as Alum adjuvant. The mechanism of the Alum adjuvant refers to the antigen being absorbed on the aluminum salt, which is also used as the immunostimulant, and when the antigen is taken up by antigen-presenting cell, the immunostimulant absorbed by the antigen stimulates the antigen-presenting cell at the same time.
Please refer to the U.S. Pat. No. 7,357,963, which is incorporated herein by reference. It disclosed a process for the manufacture of a vaccine, in which an adjuvant composition containing an immunostimulant adsorbed onto a first metallic salt particle substantially free of antigen is mixed with an antigen adsorbed onto a second metallic salt particle. The antigen is derived from human immunodeficiency virus, varicella zoster virus, human cytomegalovirus, dengue virus, hepatitis A, B, C or E virus. Actually, the Alum adjuvant is applied to over 50% of the commercial vaccine product, including hepatitis B vaccine (Alum-HBsAg), diphtheria and tetanus toxoid vaccine (Alum-DT), etc. The foregoing antigen-metal complex vaccine is used for years and it is proved that the complex is absorbed easily by the antigen-presenting cell, but it is doubted that the safety of the heavy metal. Accordingly, the safety adjuvant used in the vaccine application should be developed to avoid the unsafe problems resulting from the Alum adjuvant and to enhance the antibody production for better immune responses and lowering the administration frequency and the cost.